A Long Line of Alzheimer’s Failures: Roche Drops Two Drug Trials

Rocheannounced that it was discontinuing two of its Alzheimer’s Phase III trials, CREAD I and 2, after a pre-planned interim analysis. The studies investigated crenezumab in patients with early, prodromal to mild, sporadic Alzheimer’s disease. Roche was working with AC Immuneon developing the drug.

This is yet another failure in a long line of clinical trial failures in the Alzheimer’s space. From 1998 to 2017 there have been about 146 failed attempts at developing Alzheimer’s drugs, and 2018 marked another half-dozen or so.

Crenezumab appeared safe, but the interim analysis showed the drug was unlikely to meet the primary endpoint of change from baseline in Clinical Dementia Rating-Sum of Boxes (CDR-SB) Score. The companies expect to present the data at an upcoming medical conference.

Roche indicated that a crenezumab trial in Colombia as part of the Alzheimer’s Prevention Initiative (API) will continue. It also says it is committed to continuing work on Alzheimer’s, including Phase III trials with gantenerumab and a Phase II anti-tau trial. The Colombia trial focuses on cognitively healthy patients who have an autosomal dominant mutation that places them at risk to develop familial Alzheimer’s disease. It is a five-year trial in collaboration with the Banner Institute funded by the National Institute on Aging.

“While the results with crenezumab are disappointing, they meaningfully contribute to our understanding of Alzheimer’s disease,” stated Sandra Horning, Roche’s chief medical officer and head of Global Product Development. “We gratefully acknowledge the participants in the CREAD trials and the efforts of everyone involved in this important program. We remain dedicated to the Alzheimer’s community and will continue our Phase III GRADUATE trials with gantenerumab and Phase II TAURIEL trial with the anti-tau molecule RG6100, as well as our imaging and fluid-based diagnostic solutions.”

Crenezumab is a monoclonal antibody that binds to and promotes the removal of beta-amyloid, the plaques that accumulate in the brain early in the disease and are generally implicated in causing the brain damage that results in cognitive and memory issues. The beta-amyloid theory has come under fire in recent years because several drugs that effectively prevent beta-amyloid accumulation or remove it, did not improve cognition in clinical trials.

Rudy Tanzi, Chair of the Cure Alzheimer’s Fund Research Leadership Group and the Kennedy Professor of Neurology at Harvard University and at Massachusetts General Hospital, recently discussedAlzheimer’s with BioSpace. “I think amyloid and tangles trigger the disease,” he said, “but they’re not sufficient to cause dementia. In a nutshell, what we’ve learned is that amyloid comes very early, 15 years before symptoms. And all the genetics tells us this disease begins with amyloid.”

He noted that once amyloid starts to form, the tangles will kill some neurons, but not enough to cause dementia. By the amyloid and tangle-driven neuronal cell death eventually hits a point where the brain’s innate immune system reacts with significant levels of neuroinflammation. “Then, exponentially more cell death occurs, which leads to symptoms of dementia and Alzheimer’s disease,” he said.

Tau, on the other hand, typically occurs later on in the disease. Roche’s RG65100 is a monoclonal IgG4 antibody that binds to multiple tau species. That drug is hoped to slow the propagation of tau in Alzheimer’s disease. It is currently in a Phase II clinical trial.